The HIV epidemic continues to be one of the most serious public health problems in the US. The number of treated subjects with chronic HIV infection is increasing and with it the prevalence of HIV-associated cognitive &neurological impairment. In these patients cognitive impairment is associated with damage to the synapto-dendritic complex of mature neurons and defects in neurogenesis in adult hippocampus. Therefore, development of alternative treatments to reduce neuronal damage and rescue the alterations in neuronal stem cells (NSCs) in patients with NeuroAIDS might be of significant importance in managing the cognitive disturbances. During the previous period of funding for this grant we discovered that in patients with HIVE, neurodegeneration is associated with alterations in fibroblast growth factors (FGF) &that FGFs might protect neurons from the toxic effects of HIV proteins by inactivating the glycogen synthase kinase-3 (GSK3) signaling pathway. These studies have moved towards pilot clinical trials with lithium. More recently, we found that FGF might also be neuroprotective by regulating other intracellular cascades that are affected in patients with HIVE, such as the cyclin dependent kinase-5 (CDK5) signaling pathway. In this context, the main objectives are to: i) investigate the role of the CDK5 pathway in the mechanisms of synapto-dendritic damage and defective neurogenesis in HIVE, and ii) to test the potential neuroprotective &therapeutic effects of CDK5 inhibitors in models of HIV neurotoxicity. The central hypothesis is that HIV-derived proteins via calcium-mediated calpain activation promote the aberrant cleavage of p35 into p25 with concomitant CDK5 hyperactivation. CDK5-mediated abnormal phosphorylation of synaptic and cytoskeletal substrates might lead to neurodegeneration by interfering with synaptic plasticity and neurogenesis. To test thiswe propose: AIM 1. To investigate the role of alterations in CDK5 signaling pathway in the molecular mechanisms of synapto-dendritic damage triggered by HIV proteins. AIM 2. To determine the involvement of the CDK5 signaling pathway in the mechanisms of defective neurogenesis triggered by HIV proteins. AIM 3. To study if pharmacological inhibitors of CDK5 ameliorate synaptic pathology and alterationsin neurogenesis in in vivo models of HIV protein-mediated neurotoxicity. For this purpose, in vitro &in vivo p35-CDK5 transgenic models exposed to HIV proteins will be used. At the end of the treatments mice will be tested in water maze &neuropathologically. End points will include analysis of neurodegeneration, synaptic structure, CDK5 activity &phosphorylation state of CDK5-related substrates. Neurogenesis will be evaluated by BrdU incorporation, OCX, &PCNA expression in the hippocampus. These studies will be complemented by testing the neuroprotective effects of roscovitine andrelated analogs in primary neuronal cultures and NSCs in the presence of HIV proteins (gp120, tat, vpr), or in HIV infected mixed neuronal/microglial cultures.Together these studies will help to elucidate the role of the CDK5 pathway in neurodegeneration in patients with HIVE and help at developing new neuroprotective treatments.